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Dual-Activity Fluoroquinolone-Transportan 10 Conjugates offer alternative Leukemia therapy during Hematopoietic Cell Transplantation
Abstract
Hematopoietic cell transplantation (HCT) is often considered a last resort leukemia treatment, fraught with limited success due to microbial infections, a leading cause of mortality in leukemia patients. To address this critical issue, we explored a novel approach by synthesizing antileukemic agents containing antibacterial substances. This innovative strategy involves conjugating fluoroquinolone antibiotics, such as ciprofloxacin (CIP) or levofloxacin (LVX), with the cell-penetrating peptide (CPP) transportan 10 (TP10). Here, we demonstrate that the resultant compounds display promising biological activities in preclinical studies. These novel conjugates not only exhibit potent antimicrobial effects but are also selective against leukemia cells. The cytotoxic mechanism involves rapid disruption of cell membrane asymmetry leading to membrane damage. Importantly, these conjugates penetrated mammalian cells, accumulating within the nuclear membrane without significant effect on cellular architecture or mitochondrial function. Molecular simulations elucidated the aggregation tendencies of TP10 conjugates within lipid bilayers, resulting in membrane disruption and permeabilization. Moreover, mass spectrometry analysis confirmed efficient reduction of disulfide bonds within TP10 conjugates, facilitating release and activation of the fluoroquinolone derivatives. Intriguingly, these compounds inhibited human topoisomerases, setting them apart from traditional fluoroquinolones. Remarkably, TP10 conjugates generated lower intracellular levels of reactive oxygen species (ROS) compared to CIP and LVX. The combination of antibacterial and antileukemic properties, coupled with selective cytostatic effects and minimal toxicity towards healthy cells, positions TP10 derivatives as promising candidates for innovative therapeutic approaches in the context of antileukemic HCT. This study highlights their potential in search of more effective leukemia treatments.
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Authors (18)
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Jan Lica dr
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Mateusz Heldt
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Natalia Ptaszyńska
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Anna Łęgowska
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Katarzyna Gucwa Dr inż.
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Bhaskar Pradhan
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Agata Gitlin-Domagalska
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Dawid Dębowski
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Grzegorz Jan Grabe dr
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Andrzej Hellmann prof. dr hab. n. med.
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Rolka Krzysztof
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Details
- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
-
MOLECULAR PHARMACOLOGY
no. 105,
pages 39 - 53,
ISSN: 0026-895X - Language:
- English
- Publication year:
- 2024
- Bibliographic description:
- Lica J., Heldt M., Wieczór M., Chodnicki P., Ptaszyńska N., Łęgowska A., Brankiewicz W., Gucwa K., Stupak A., Maciejewska N., Pradhan B., Gitlin-Domagalska A., Dębowski D., Milewski S., Bieniaszewska M., Grabe G. J., Hellmann A., Krzysztof R.: Dual-Activity Fluoroquinolone-Transportan 10 Conjugates offer alternative Leukemia therapy during Hematopoietic Cell Transplantation// MOLECULAR PHARMACOLOGY -,iss. 05 (1) (2024), s.39-53
- DOI:
- Digital Object Identifier (open in new tab) 10.1124/molpharm.123.000735
- Sources of funding:
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- The financial support to maintenance of research facilities used in these studies from Gdańsk University of Technology by the DEC--2/2021/IDUB/V.6/Si grant under the SILICIUM SUPPORTING CORE R&D FACILITIES – “Excellence Initiative - Research University”
- Verified by:
- Gdańsk University of Technology
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